EP0465535A1 - Regioselective substitutions in cyclodextrins - Google Patents
Regioselective substitutions in cyclodextrinsInfo
- Publication number
- EP0465535A1 EP0465535A1 EP90905461A EP90905461A EP0465535A1 EP 0465535 A1 EP0465535 A1 EP 0465535A1 EP 90905461 A EP90905461 A EP 90905461A EP 90905461 A EP90905461 A EP 90905461A EP 0465535 A1 EP0465535 A1 EP 0465535A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substitution
- cyclodextrins
- hydroxyalkylated
- regiospecifically
- hydroxyl groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Definitions
- cyclic oligosaccharides e.g. ⁇ -, ⁇ - or ⁇ - cyclodextrins
- the shape of cyclodextrins is a toroid : on the narrower side of the toroids are located all primary hydroxyls (-CH 2 -OH) and on the wider sides are the secondary hydroxyls.
- cyclodextrins in inclusion complexation : a guest lipophilic compound is accepted into the toroidal cavity of the host compound, i.e., of the cyclodextrin. This process is bound to be affected by specific changes at the entry sites of the host molecule. That was well demonstrated using chemically pure cyclodextrin derivatives. These compounds were prepared by multi-step synthesis requiring multiple extensive purifications and thus are available only in small quantities and at a great price.
- cyclodextrin derivatives In many applications the chemical purity (individuality) of cyclodextrin derivatives is not required or may even be of a detriment. Using mixtures of cyclodextrins is often preferred since these usually do not crystallize and thus have much higher solubilities and are also better suited as coatings.
- Cyclodextrins such as ⁇ -, ⁇ - or ⁇ -cyclodextrins, similarly to other carbohydrates, react with epoxides yielding mixtures of oligosubstituted hydroxyalkylcyclodextrins.
- the latter compounds were first disclosed U.S. Patent 3,459,731. These cyclodextrins were found eminently useful for pharmaceutical purposes and this use was disclosed in U.S. Patent 4,596,795, U.S. 4,727,064, U.S. Patent 4,870,060, U.S. Patent
- the concentration of sodium hydroxide solution which is used as a solvent for the other component, ranged between 5-17% w/w preferably about 11% w/w. At concentrations lower than these the reaction proceeds sluggishly; at higher concentrations the solubility of ⁇ -cyclodextrin decreases and also the removal of sodium hydroxide after the reaction becomes tedious. Thus, in production of hydroxyalkylcyclodextrins the practical range of the concentrations of sodium hydroxide solution used as a solvent were 5-17% and there was no incentive to venture outside of this range.
- the aim of the present invention is to provide a process enabling the attainment of a desired pattern of substitution by hydroxyalkyl groups onto ⁇ -, ⁇ - or - ⁇ -cyclodextrins through the control of basicity of the reaction mixtures which are comprised of epoxide and cyclodextrins and a suitable solvent It was found that through the proper control of basicity the substitution may be directed either toward the wide or the narrow opening of the cavity of cyclodextrins i.e. (1) toward hydroxyls 2 or 2,3 of glucose residues with little substitution on hydroxyl 6, or (2) toward hydroxyl 6 and with little substitution on the secondary hydroxyls 2 and 3.
- the basicity of the reaction mixtures required for said regiospecificity may be obtained by a decrease or an increase of the previously used concentration range (5-17%) of sodium hydroxide solution, which is used as a reaction solvent for other components of the reaction mixtures. These concentrations represent typically less than 2.5% or more than 10.5% of sodium hydroxide content in the fully assembled reaction mixtures.
- the desired basicity may preferably be obtained using sodium methylsulf ⁇ nylmethanide as a base and dimethyl sulfoxide as a solvent. It is however understood that other organic solvents or bases may be applied.
- the above method may also be applied for the preparation of mixtures of hydroxyalkylcyclodextrins which vary in their average degree of substitution, but in which the pattern of substitution is not changed.
- a further aspect of the invention is to provide regiospecific hydroxyalkylated ⁇ -, ⁇ - or ⁇ -cyclodextrins wherein the substitution is mainly on the hydroxyls 2 or 2,3 of the glucose residues with little substitution on hydroxyl 6, or wherein the substitution is mainly on the hydroxyl 6 with little substitution on the secondary hydroxyls 2 and 3, and fully or partly alkylated derivatives of these regiospecific hydroxyalkylated ⁇ -, ⁇ - or ⁇ - cyclodextrins.
- Particular hydroxyalkylcyclodextrins substituted mainly on the wide side of the cavity have a relative distribution of the substitution on the 2 hydroxyl groups versus the 6 hydroxyl groups which varies from about 2:1 to about 20:1, preferably from about 5:1 to about 20:1, or from about 10:1 to about 15:1.
- Particular hydroxyalkylcyclodextrins substituted mainly on the wide side of the cavity have a relative distribution of the substitution on the 2 hydroxyl groups versus the 6 hydroxyl groups which varies from about 2:1 to about 20:1, preferably from about 5:1 to about 20:1, or from about 10:1 to about 15:1.
- hydroxyalkyl defines bivalent straight or branch chained hydrocarbon radicals containing form 1 to 6 carbon atoms such as hydroxyethyl, hydroxypropyl or hydroxyisobutyl groups.
- the average molar substitution is used as a measure of the average number of alkylated hydroxy functions per mole of glucose unit
- Particular cyclodextrins according to the present invention have a M;S. which is in the range of 0.125 to 10, in particular of 0.3 to 3, or from 0.3 to 1.5.
- the average substitution degree (D.S.) expresses the average number of substituted hydroxyls per glucose unit
- Particular cyclodextrins according to the present invention have a D.S. which is in the range of 0.125 to 3, in particular of 0.2 to 2, or from 0.2 to 1.5.
- Hydroxyalkylated ⁇ -, ⁇ - or ⁇ -cyclodextrins are prepared by an alkali catalyzed reaction of epoxides with cyclodextrins in a suitable solvent preferably at a temperature between 0 to 100°C or between 0 to 70°C.
- a suitable solvent for carrying out the process of the invention is an aqueous alkali metal hydroxide solution.
- the alkali metal hydroxide used may be mentioned lithium hydroxide, barium hydroxide, sodium hydroxide and potassium hydroxide. Of these, sodium hydroxide is preferable.
- the concentration of the sodium hydroxide solution which is used as a reaction solvent for other components of the reaction mixtures is either lower than 5% (w/w), preferably lower than 4% (w/w), or higher than 17%(w/w), preferably higher than 18%(w/w). In some instances, equinormal lithium, potassium or barium hydroxide solutions may also be applied. These concentrations represent typically less than 2.5% or more man 10.5% of alkali metal hydroxide content in the fully assembled reaction mixtures.
- the molar ratio of alkali metal hydroxide versus cyclodextrin should preferably be in the range of 0.5 to 3.5, more in particular less than 2.5, or should be in the range of 10 to 80, more in particular more than 13.8.
- the epoxide concentration in the final mixture may vary from about 1% to about 30%, more in particular from about 2% to about 20%.
- Particular samples of hydroxypropylated ⁇ -cyclodextrin were prepared by reacting ⁇ -cyclodextrin with propylene oxide in aqueous sodium hydroxide (Examples 1-7). The reaction conditions used in these preparations are summarized in Table I.
- a suitable solvent for carrying out the present invention may also dimethyl sulfoxide, N,N-dim ethylformamide, dioxane or mixtures thereof with water in the presence of a base. It is however understood that other organic solvents or bases may be applied.
- anhydrous conditions were used with sodium methylsulf ⁇ nylmethanide in dimethylsulfoxide as catalyst and solvent, respectively. Pure regiospecific hydroxypropylated cyclodextrin may be isolated from the mixtures by removal of the unreacted starting material by art known procedures such as, extraction with organic solvents, adsorption chromatograpy, selective crystallization and combinations of these techniques.
- each product was permethylated (Example 9), hydrolysed, and the resulting glucose ethers reduced, acetylated, and analyzed as alditol acetates, by gas liquid chromatography (Example 10).
- Etherification with an epoxide such as propylene oxide is a complicated reaction. When racemic propylene oxide is used, diastereomeric ethers are formed, which are only partially separated by the analytical method used.
- Examples 1-3 were prepared using racemic propylene oxide, whereas in Examples 4-8 (S)-propylene oxide was used, which is bound to yield a simpler pattern.
- Another complication is that the oxiran ring in propylene oxide can be opened either by attack on 0-1, which is the predominating reaction and gives a
- S 2 denotes mono-substitution on 0-2
- S 226 denotes bi-substitution on 0-2 (by -CH 2 -C(CH 3 )H-O-CH 2 -CH(OCH 3 )-CH 3 group) and mono-substitution on 0-6; glucose-derived numbering was used for alditols. In some analyses under methylation, especially in the 3-position, was observed. The products, however, were identified from their mass spectra, and the molar percentages added to those of the corresponding fully methylated components. Two 2-(1-methoxy- propyl) ethers were observed with this group in the 2- and the 6-position of a glucosyl residue, respectively. The yields of these ethers were 2-4% of the corresponding 1-(2-methoxy ⁇ ropyl)ethers, and reflects the relative reactivities at the primary and the secondary position of propylene oxide, respectively.
- the relative reactivities at the three different positions in the ⁇ -D-glucopyranosyl groups may be determined from the molar percentages of the ethers.
- Sperlin equations H.M. Sperlin in E. Ott, H.M. Sperlin and M.W. Graf ⁇ lin (Eds.) Cellulose and
- the thus prepared regiospecific hydroxyalkylated cyclodextrins may also be derivatized with an alkylating agent to obtain fully or partly substituted mixed ethers.
- the alkylation reaction may be carried out with appropriate alkylating agents such as alkylsulfates or alkylhalogenides in a base, liquid reaction medium containing an alkali metal hydroxide, water and, optionally, at least one organic solvent such as, for example, dimethoxyethane or isopropanol.
- appropriate alkylating agents such as alkylsulfates or alkylhalogenides in a base, liquid reaction medium containing an alkali metal hydroxide, water and, optionally, at least one organic solvent such as, for example, dimethoxyethane or isopropanol.
- ⁇ -Cyclodextrin 200 g of hydrate corresponding to 173.2 g anhydrous and 0.153 moles was dissolved with stirring in warm (60°C) solution of sodium hydroxide (61.2 g or 0.53 moles in 300 ml of distilled water, i.e., 16.9% w/w). The solution was placed into round flask, cooled to ice bath temperature and after attachment of reflux condenser containing dry ice-acetone mixture, propylene oxide (25 ml, 23.2 g, 0.40 moles) was added dropwise with constant stirring. Stirring was continued for 3 hours at ice bath temperature and overnight at room temperature.
- ⁇ -Cyclodextrin 200 g hydrate, i.e., 173 g anhydrous, 0.153 moles
- sodium hydroxide 85 g, 2.12 moles in 400 ml distilled water, i.e., 17.5% w/w
- propylene oxide 150 ml, 125 g, 2.152 moles.
- a fraction of oligopropylene glycols amounted to 38 g while altogether 193 g of hydroxypropyl- ⁇ - cyclodextrin was obtained.
- ⁇ -Cyclodextrin 500 g hydrate, i.e., 432 g anhydrous, 0.382 moles
- a solution of sodium hydroxide 45 g, 1.1 moles in 750 ml distilled water, i.e., 5.7% w/w
- propylene oxide 260 ml, 217 g, 3.73 moles
- the reaction mixture was left for five hours in an ice bath and kept at room temperature for two days. After processing similar to that described above and including extraction of oligopropylene glycols with acetone a white powder of hydroxypropyl- ⁇ -cyclodextrin (490 g) was obtained.
- ⁇ -Cyclodextrin (13.3 g of hydrate, i.e., 11.5 g anhydrous, 0.010 moles) was dissolvedin a solution of sodium hydroxide (0.822 g, 0.0206 mol in 54 ml distilled water, i.e., 1.5%) by stirring at 60°C.
- the increased amount of alkaline solution used was necessitated by the low solubility of ⁇ -cyclodextrin at very low (present case) or very high (30%) concentration of sodium hydroxide.
- the solution was cooled in an ice bath and in the same manner as above (S)-propylene oxide (10 ml, 8.29 g, 0.143 moles), a commercial preparation obtained from Aldrich Chemical Co., was added.
- ⁇ -Cyclodextrin (13.3 g of hydrate, i.e., 11.5 g anhydrous, 0.010 moles) was dissolved in a process as described above in a solution of sodium hydroxide (1.35 g, 0.034 moles in 27 ml distilled water, i.e., 4.8%) and treated in the manner described above with (S)-propylene oxide (10 ml, 8.29 g, 0.143 moles). The reaction mixture was kept overnight at 0-5°C and thereafter for 3 hours at room temperature. After neutralization with diluted sulfuric acid (10%) the solution was evaporated in vacuo nearly to dryness and residue stirred with ethanol (100 ml, 190 proof) for 30 minutes.
- ⁇ -Cyclodextrin (8.02 g hydrate, 6.93 g anhydrous, 6.1 moles) was added to a solution of sodium hydroxide (13.955 g, 0.349 moles in water 32.6 ml, i.e., 30%) and dissolved by stirring and heating to 70°C to a clear yellowish solution. Then the mixture was cooled in an ice bath and to the solution which remained homogeneous was added, while stirring, (S)-propylene oxide (5 g, 0.086 moles). After neutralization, evaporation, ethanol extraction, and dialysis all performed as above, a white powdery product (9.22 g) was obtained.
- the permetltylated product (3 mg) was dissolved in M aqueous trifluoroacetic acid (0.5 ml), kept in a screw-cap tube at 100°C overnight and concentrated by flushing with air.
- the residue and sodium borohydride (10 mg) were dissolved in M aqueous ammonia (05 ml) and kept at room temperature for 1 hour.
- the solution was acidified with 50% acetic acid (2 drops) and concentrated. Boric acid was removed by codistillation first with acetic acid-methanol (1:9, 5 ml) and then with methanol (25 ml).
- G.l.c. was performed on a Hewlett Packard 5830 A instrument fitted with a flame ionization detector, with hydrogen as the carrier gas.
- G.l.c.-m.s. was performed on a Hewlett Packard 5790-5970 system with helium as the carrier gas.
- Temperature program 8 minutes at 185°C, ⁇ 250°C at 5° per minute, 250°C for 10 minutes.
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33260689A | 1989-04-03 | 1989-04-03 | |
US332606 | 1989-04-03 | ||
PCT/EP1990/000524 WO1990012035A1 (en) | 1989-04-03 | 1990-03-30 | Regioselective substitutions in cyclodextrins |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0465535A1 true EP0465535A1 (en) | 1992-01-15 |
EP0465535B1 EP0465535B1 (en) | 1998-06-03 |
Family
ID=23298989
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90905461A Expired - Lifetime EP0465535B1 (en) | 1989-04-03 | 1990-03-30 | Regioselective substitutions in cyclodextrins |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0465535B1 (en) |
JP (1) | JP2792610B2 (en) |
KR (1) | KR0163440B1 (en) |
AT (1) | ATE166884T1 (en) |
AU (1) | AU631628B2 (en) |
CA (1) | CA2047726C (en) |
DE (1) | DE69032370T2 (en) |
DK (1) | DK0465535T3 (en) |
ES (1) | ES2116982T3 (en) |
FI (1) | FI101385B1 (en) |
HK (1) | HK1009335A1 (en) |
HU (1) | HUT58770A (en) |
NO (1) | NO304269B1 (en) |
WO (1) | WO1990012035A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE44733E1 (en) | 1999-11-29 | 2014-01-28 | Merck Sharp & Dohme B.V. | 6-mercapto-cyclodextrin derivatives:reversal agents for drug-induced neuromuscular block |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4401618A1 (en) * | 1994-01-20 | 1995-07-27 | Consortium Elektrochem Ind | New or known amino-functional cyclodextrin deriv. prepn. |
DE19505263A1 (en) * | 1995-02-16 | 1996-08-22 | Consortium Elektrochem Ind | Process for the purification of water-soluble cyclodextrin derivatives |
US6683100B2 (en) | 1999-01-19 | 2004-01-27 | Novartis Ag | Organic compounds |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
US6197294B1 (en) | 1998-10-26 | 2001-03-06 | Neurotech S.A. | Cell surface molecule-induced macrophage activation |
DK2272503T3 (en) | 2003-03-28 | 2013-05-21 | Ares Trading Sa | Oral formulations of cladribine |
CN101912615B (en) | 2003-03-28 | 2013-03-27 | 阿莱斯贸易有限公司 | Cladribine formulations for improved oral and transmucosal delivery |
UA81305C2 (en) | 2003-07-02 | 2007-12-25 | Ares Trading Sa | Formulation of cladribine (variants), cladribine-cyclodextrin complex, use of cladribine-cyclodextrin complex, mixture |
US7635773B2 (en) | 2008-04-28 | 2009-12-22 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
PL3702374T3 (en) | 2012-02-15 | 2022-11-21 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
RU2747757C2 (en) | 2012-02-28 | 2021-05-13 | Сидекс Фармасьютикалс, Инк. | Compositions of alkylated cyclodextrin and methods of their preparation and application |
CN105073785B (en) | 2012-10-22 | 2018-08-21 | 锡德克斯药物公司 | Alkylated cyclodextrin composition and its preparation and application |
EP3183295B1 (en) | 2014-08-22 | 2023-08-02 | CyDex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
JP2019163344A (en) * | 2016-07-25 | 2019-09-26 | 国立大学法人 東京大学 | Pseudo-polyrotaxane, polyrotaxane, and manufacturing method therefor |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3459731A (en) * | 1966-12-16 | 1969-08-05 | Corn Products Co | Cyclodextrin polyethers and their production |
DE2260785A1 (en) * | 1972-12-12 | 1974-06-20 | Morishita Pharma | Prepn of hydroxyethyl starches - using organic base catalyst useful as blood serum extenders |
EP0146841A3 (en) * | 1983-12-17 | 1986-11-20 | Consortium für elektrochemische Industrie GmbH | Water soluble mixed ether of beta-cyclodextrin, and process for its preparation |
US4727064A (en) * | 1984-04-25 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Pharmaceutical preparations containing cyclodextrin derivatives |
GB8506792D0 (en) * | 1985-03-15 | 1985-04-17 | Janssen Pharmaceutica Nv | Derivatives of y-cyclodextrin |
AU7453191A (en) * | 1990-03-02 | 1991-09-18 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
-
1990
- 1990-03-30 EP EP90905461A patent/EP0465535B1/en not_active Expired - Lifetime
- 1990-03-30 WO PCT/EP1990/000524 patent/WO1990012035A1/en active IP Right Grant
- 1990-03-30 ES ES90905461T patent/ES2116982T3/en not_active Expired - Lifetime
- 1990-03-30 KR KR1019910701230A patent/KR0163440B1/en not_active IP Right Cessation
- 1990-03-30 AT AT90905461T patent/ATE166884T1/en not_active IP Right Cessation
- 1990-03-30 HU HU902934A patent/HUT58770A/en unknown
- 1990-03-30 DE DE69032370T patent/DE69032370T2/en not_active Expired - Lifetime
- 1990-03-30 JP JP2505324A patent/JP2792610B2/en not_active Expired - Fee Related
- 1990-03-30 CA CA002047726A patent/CA2047726C/en not_active Expired - Lifetime
- 1990-03-30 AU AU53587/90A patent/AU631628B2/en not_active Expired
- 1990-03-30 DK DK90905461T patent/DK0465535T3/en active
-
1991
- 1991-10-02 FI FI914620A patent/FI101385B1/en active
- 1991-10-02 NO NO913871A patent/NO304269B1/en not_active IP Right Cessation
-
1998
- 1998-08-18 HK HK98109960A patent/HK1009335A1/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of WO9012035A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE44733E1 (en) | 1999-11-29 | 2014-01-28 | Merck Sharp & Dohme B.V. | 6-mercapto-cyclodextrin derivatives:reversal agents for drug-induced neuromuscular block |
Also Published As
Publication number | Publication date |
---|---|
HUT58770A (en) | 1992-03-30 |
JP2792610B2 (en) | 1998-09-03 |
JPH04504275A (en) | 1992-07-30 |
DE69032370D1 (en) | 1998-07-09 |
AU631628B2 (en) | 1992-12-03 |
FI914620A0 (en) | 1991-10-02 |
KR0163440B1 (en) | 1998-11-16 |
ES2116982T3 (en) | 1998-08-01 |
HU902934D0 (en) | 1991-12-30 |
DK0465535T3 (en) | 1999-03-01 |
EP0465535B1 (en) | 1998-06-03 |
CA2047726C (en) | 2001-04-17 |
NO913871L (en) | 1991-10-02 |
AU5358790A (en) | 1990-11-05 |
KR920701258A (en) | 1992-08-11 |
HK1009335A1 (en) | 1999-05-28 |
NO913871D0 (en) | 1991-10-02 |
NO304269B1 (en) | 1998-11-23 |
DE69032370T2 (en) | 1998-10-29 |
FI101385B (en) | 1998-06-15 |
ATE166884T1 (en) | 1998-06-15 |
FI101385B1 (en) | 1998-06-15 |
WO1990012035A1 (en) | 1990-10-18 |
CA2047726A1 (en) | 1990-10-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5096893A (en) | Regioselective substitutions in cyclodextrins | |
EP0536318B1 (en) | Regioselective substitutions in cyclodextrins | |
EP0465535B1 (en) | Regioselective substitutions in cyclodextrins | |
Pitha et al. | Distribution of substituents in 2-hydroxypropyl ethers of cyclomaltoheptaose | |
Szente et al. | Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development | |
US4582900A (en) | Water-soluble mixed ethers of β-cyclodextrin and a process for their preparation | |
Rao et al. | Substitution in. beta.-cyclodextrin directed by basicity: preparation of 2-O-and 6-O-[(R)-and (S)-2-hydroxypropyl] derivatives | |
US5935941A (en) | Alkylations of cyclodextrins leading to derivatives which have a ridgidly extended cavity | |
Qu et al. | Sulfoalkyl ether β-cyclodextrin derivatives: synthesis and characterizations | |
Lee et al. | Oligosaccharide synthesis by the thioglycoside scheme on soluble and insoluble polystyrene supports | |
Irie et al. | Amorphous water-soluble cyclodextrin derivatives: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisobutyl, and carboxamidomethyl derivatives of β-cyclodextrin | |
Pitha et al. | Cyclodextrin sulfates: characterization as polydisperse and amorphous mixtures | |
EP0868438B1 (en) | Selective alkylations of cyclodextrins at the levels of minimal effective basicity | |
EP1272531B8 (en) | Crystalline mixtures of partial methyl ethers of beta-cyclodextrin and related compounds | |
Deratani et al. | 2-hydroxy-3-trimethylammoniopropyl derivatives of cyclomaltoheptaose as phase-transfer catalysts | |
Rao et al. | Pharmaceutical Usefulness of Hydroxypropylcyclodextrins:" E Pluribus Unum” Is an Essential Feature | |
Singh et al. | Complexation of 6-Deoxy-6-(aminoethyl) amino-β-cyclodextrin with Sodium Cholate and Sodium Deoxycholate | |
Bansal et al. | Regioselective alkylation of β-cyclodextrin | |
HUT64979A (en) | Method for producing (carboxy)-alkoxy-alkyl derivatives of cyclodextrines | |
WO2024057083A1 (en) | Process for the synthesis of selectively alkylated cyclodextrins | |
WO1999045032A1 (en) | Novel derivatives of cyclodextrins | |
CA2333262C (en) | Regioselective method for preparing cyclodextrin derivatives monosulfonylated at c-6 | |
KR101557413B1 (en) | - A composition and a method for improving solubility and bioavailability of -naphthoflavone | |
HU195524B (en) | Process for the alkylation of cyclodextrins | |
HU202889B (en) | Process for producing 2-hydroxi-propyl-alpha-, beta- and gamma- cyclodextrine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19910823 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB IT LI LU NL SE |
|
17Q | First examination report despatched |
Effective date: 19930329 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB IT LI LU NL SE |
|
REF | Corresponds to: |
Ref document number: 166884 Country of ref document: AT Date of ref document: 19980615 Kind code of ref document: T |
|
ITF | It: translation for a ep patent filed |
Owner name: JACOBACCI & PERANI S.P.A. |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REF | Corresponds to: |
Ref document number: 69032370 Country of ref document: DE Date of ref document: 19980709 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: E. BLUM & CO. PATENTANWAELTE |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2116982 Country of ref document: ES Kind code of ref document: T3 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
PLBQ | Unpublished change to opponent data |
Free format text: ORIGINAL CODE: EPIDOS OPPO |
|
PLBI | Opposition filed |
Free format text: ORIGINAL CODE: 0009260 |
|
PLBF | Reply of patent proprietor to notice(s) of opposition |
Free format text: ORIGINAL CODE: EPIDOS OBSO |
|
26 | Opposition filed |
Opponent name: CERESTAR HOLDING B.V. Effective date: 19990302 |
|
NLR1 | Nl: opposition has been filed with the epo |
Opponent name: CERESTAR HOLDING B.V. |
|
PLBF | Reply of patent proprietor to notice(s) of opposition |
Free format text: ORIGINAL CODE: EPIDOS OBSO |
|
PLBF | Reply of patent proprietor to notice(s) of opposition |
Free format text: ORIGINAL CODE: EPIDOS OBSO |
|
PLBL | Opposition procedure terminated |
Free format text: ORIGINAL CODE: EPIDOS OPPC |
|
PLBM | Termination of opposition procedure: date of legal effect published |
Free format text: ORIGINAL CODE: 0009276 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: OPPOSITION PROCEDURE CLOSED |
|
27C | Opposition proceedings terminated |
Effective date: 20000303 |
|
NLR2 | Nl: decision of opposition | ||
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PFA Owner name: JANSSEN PHARMACEUTICA N.V. Free format text: JANSSEN PHARMACEUTICA N.V.#TURNHOUTSEWEG 30#2340 BEERSE (BE) -TRANSFER TO- JANSSEN PHARMACEUTICA N.V.#TURNHOUTSEWEG 30#2340 BEERSE (BE) |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20081215 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DK Payment date: 20090313 Year of fee payment: 20 Ref country code: AT Payment date: 20090313 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20090303 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20090325 Year of fee payment: 20 Ref country code: CH Payment date: 20090331 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20090428 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20090306 Year of fee payment: 20 Ref country code: IT Payment date: 20090320 Year of fee payment: 20 Ref country code: DE Payment date: 20090327 Year of fee payment: 20 Ref country code: LU Payment date: 20090522 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20090316 Year of fee payment: 20 |
|
BE20 | Be: patent expired |
Owner name: *JANSSEN PHARMACEUTICA N.V. Effective date: 20100330 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EUP |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20100329 |
|
EUG | Se: european patent has lapsed | ||
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20100331 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20100329 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20100331 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: V4 Effective date: 20100330 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20100330 |